Project Summary The molecular study of cognition has been revolutionized by the discovery of experience-dependent epigenetic remodeling. The mechanisms underlying these processes have been implicated in autism spectrum disorders and other forms of intellectual disability that are associated with communication deficits. Epigenetic mechanisms are promising therapeutic targets for developmental disorders because they could potentially enhance the efficacy of environmental interventions such as speech therapy. Songbirds are the commonly used model for human speech, as they allow for behavioral experiments designed to understand the molecular basis of learned vocal communication. Unlike other model organisms, zebra finches learn complex vocalizations from observing adults in the social environment. Work from our lab and others reveals that dynamic behavioral regulation of song- and language-related genes such as FoxP2 underlies learned vocal communication, but the mechanistic basis for this awaits further characterization. We previously used Weighted Gene Co-Expression Network Analysis to show that in the striatal song nucleus Area X, changes in the expression of histone H3 methylation erasers, microRNA-128, and the transcriptional regulator histone variant H3.3 are significantly correlated with singing. In contrast, these changes are not observed in a neighboring striatal region that does not control song. From this data set I developed a working model whereby singing induces activity-dependent miR-128 expression, which then alters repressive transcriptional machinery levels in order to expose certain song-regulated genes for H3.3 exchange and transcriptional activation. To test this hypothesis, I raised zebra finches in isolation such that they developed an impoverished song. I then reintroduced them as adults to a tutor and administered daily treatments of the miR-128 activator ginsenoside Rh2 (GRh2) or vehicle as a control. Excitingly, GRh2 significantly ameliorated deficits in syntax stereotypy, allowing the bird to organize his song and reproduce it with high fidelity. I will investigate how GRh2 rescues communication deficits by first characterizing the social isolate model using RNA sequencing and chromatin immunoprecipitation sequencing. I will then generate a siRNA construct to knock down miR-128 in Area X and analyze how this affects song and gene expression using RNAseq. I will then rescue social isolation-induced communication deficits with GRh2 and compare the results to an HDAC inhibitor, a class of drugs that has shown promise in animal models of intellectual disability as well as human patients. This study will break new ground by testing the links between dynamic chromatin changes and learned vocal communication and introduce GRh2 as a novel epigenetic therapeutic for cognitive disorders.